DESCRIPTION: This project seeks to develop small, single chain, intra- cellular antibodies (intrabodies) against the multi-repeat glutamine regions of proteins associated with certain neurological diseases such as Huntington's. These intrabodies would target the proteins for destruction immediately after they are assembled, thus eliminating their destructive effects, but not causing damage to the cell. The Phase I application would seek to develop immortalized cell lines from transgenic mice which produce multi-repeat glutamine proteins. The second aim is to produce and examine synthetic peptides containing 20, 40 and 60 glutamine repeats. They are seeking to understand conformational changes, induced by the glutamine repeats, which may effect antibody binding. Third, a large library would be screened against the synthetic peptides to select those phages linked to antibodies which have affinity for the peptides. Multiple pannings would be performed to select the highest affinity antibodies. Actual association and dissociation constants would be evaluated by biosensory analysis. The final studies would test the efficacy of the intrabodies at removing the multi-repeat glutamine proteins from the cell lines established earlier in the project. Preliminary studies indicate that it is possible to raise such targeted intrabodies. PROPOSED COMMERCIAL APPLICATION: These regents, and drugs derived from them, could be used to treat several neurodegenerative disorders caused by repeat expansions.